Gastric cancer is the second most frequent cause of death from cancer in the world, diffuse-type gastric cancer (DGC) exhibiting a poor prognosis. Germline mutations of CDH1, encoding E-cadherin, have been reported in hereditary DGCs, and genetic and/or epigenetic alterations of CDH1 are frequently detected in sporadic DGCs. Genetic alterations of TP53 are also frequently found in DGCs. To examine the synergistic effect of loss of E-cadherin and p53 on gastric carcinogenesis, we established a mouse line in which E-cadherin and p53 are specifically inactivated in the stomach parietal cell lineage.

Intramucosal cancers and invasive cancers composed of poorly differentiated carcinoma cells and signet ring cells, histologically very similar to those in humans, were found from 6 and 9 months, respectively. Fatal DGCs developed at 100% penetrance within a year, and frequently metastasised to lymph nodes. Gene expression profiles of DGCs in the double conditional knockout (DCKO) mice also resembled those of human DGCs.

Our mouse line is the first genetically engineered mouse model of DGC and very useful for clarifying the mechanism underlying gastric carcinogenesis, and provides a new approach to the treatment and prevention of DGC.

Synergistic tumour suppressor activity of E-cadherin and p53 in a conditional mouse model for metastatic diffuse-type gastric cancer

Shu Shimada, Ayako Mimata, Masaki Sekine, Kaoru Mogushi, Yoshimitsu Akiyama, Hiroshi Fukamachi, Jos Jonkers, Hiroshi Tanaka, Yoshinobu Eishi, Yasuhito Yuasa
Gut, in press.
Gut doi:10.1136/gutjnl-2011-300050.